Genetic Causes of Hypophosphatemia
In 2006, we identified the genetic defect underlying the childhood disorder hereditary hypophosphatemic rickets with hypercalciuria (HHRH). HHRH is caused by mutations in NaPi-IIc, a renal sodium-phosphate co-transporter, which is important to conserving phosphate in the kidney and leads to hypophosphatemia and rickets when lost. Our research goal is now to study the role of NaPi-IIc in human phosphate homeostasis and to understand the phenotypic variability of patients suffering from HHRH. For this purpose, we are currently using mammalian and Xenopus oocyte expression systems to study the functional properties of the identified human NaPi-IIc mutations in vitro. Plans for the near future are to establish mouse models to study the role of NaPi-IIc and some of the human mutations in vivo.
We also established international collaborations to look for NaPi-IIc mutations in new patients suffering from HHRH both to establish their molecular diagnosis and to carefully study their symptoms to see whether only some or all patients are at risk for developing kidney stones.
Metabolic and homeostatic effects of phosphate
A more recent research interest is in trying to understand how human and other metazoan cells sense inorganic phosphate to explain the effects of phosphate on:
For this purpose, we have performed a genome-wide Drosophila RNAi knockdown using phosphate-induced activation of MAPK (in vitro) in collaboration with Stephanie Mohr, Elizabeth Perkins and Norbert Perrimon of Harvard Medical School. We identified 103 genes, including 85 phosphate-specific genes and evaluated the genes in live flies with assays for dietary phosphate toxicity, hemolymph phosphate and life span. Our goal in the next five years will be to identify mammalian systems suitable to study phosphate sensing. The team will also continue exploring Drosophila melanogaster as a model organism. Relevant readouts for humans will be the homeostatic regulation of the synthesis and secretion of PTH, 1,25-D and FGF23 by phosphate and its metabolic effect on life-span in genetic disorders, such as familial hyperphosphatemic tumoral calcinosis (FHTC) and chronic kidney disease.
I attend on the endocrine consult service at Massachusetts General Hospital and see outpatients with a focus on disorders of minerals and metabolism as a member of the Mass General Endocrine Associates. Furthermore, I also participate as faculty in the annual endocrine postgraduate course in Boston.
Past and Current Funding:
Harald Jüppner, MD
Chief, Pediatric Nephrology
MassGeneral Hospital for Children
Stuart A. Forman, MD, PhD
Henry K. Beecher Pharmacology Laboratory
Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine
Norbert Perrimon, PhD
Department of Genetics
Harvard Medical School, Howard Hughes Medical Institute
View Laboratory of Norbert Perrimon, PhD
Bonnie Berger, PhD
Computation and Biology Group, Computer Science and Artificial Intelligence Lab, MIT
Roles of major facilitator superfamily transporters in phosphate response in Drosophila. Bergwitz C, Rasmussen MD, Derobertis C, Wee MJ, Sinha S, Chen HH, Huang J, and Perrimon N. PLoS One 7: e31730, 2012.
Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: Long-term follow-up in one kindred. Yu Y, Sanderson SR, Reyes M, Sharma A, Dunbar N, Srivastava T, Jüppner H, and Bergwitz C. Bone 50: 1100-1106, 2012.
Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis. Bergwitz C, Banerjee S, Abu-Zahra H, Kaji H, Miyauchi A, Sugimoto T, Jüppner H. J Clin Endocrinol Metab. 2009 Nov;94(11):4267-74. Epub 2009 Oct 16.PMID: 19837926
A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Page K, Bergwitz C, Jaureguiberry G, Harinarayan CV, Insogna K. Endocr Pract. 2008 Oct;14(7):869-74.PMID: 18996815
Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. Sitara D, Kim S, Razzaque MS, Bergwitz C, Taguchi T, Schüler C, Erben RG, Lanske B. PLoS Genet. 2008 Aug 8;4(8):e1000154.PMID: 18688277
A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Jaureguiberry G, Carpenter TO, Forman S, Jüppner H, Bergwitz C. Am J Physiol Renal Physiol. 2008 Aug;295(2):F371-9. Epub 2008 May 14.PMID: 18480181
SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Jüppner H. Am J Hum Genet. 2006 Feb;78(2):179-92. Epub 2005 Dec 9.PMID: 16358214
Selected Reviews and Book Chapters
Dietary phosphate modifies lifespan in Drosophila. Bergwitz C Nephrol Dial Transplant 2012 Nephrol Dial Transplant 27: 3399–3406
FGF23 and syndromes of abnormal renal phosphate handling. Bergwitz C, Jüppner H. Adv Exp Med Biol. 2012;728:41-64.
Phosphate sensing. Bergwitz C, Jüppner H Adv Chronic Kidney Dis 2011;18:132
Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Bergwitz C, Jüppner H. Annu Rev Med. 2010;61:91-104.
Disorders of Phosphate Homeostasis and Tissue Mineralisation. Bergwitz C, Jüppner H. Endocr Dev. 2009;16:133-156.
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